# NM_013432.5(TONSL):c.726C>T (p.Ser242=)

https://sugi.bio/variant/tonsl-p-ser242

## Summary

**TONSL p.Ser242= (c.726C>T)** is classified **Benign** in TONSL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-15). Rare (popmax 0.729%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs112264814 · 4 submitters · rare (popmax 0.729%, afr)

## For patients & families {#patients}

This is a change in the TONSL gene that is classified as benign — not considered disease-causing, submitted by 4 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TONSL](https://sugi.bio/atlas/gene/TONSL/) |
| Protein change (HGVS p.) | p.Ser242= |
| Coding change (HGVS c.) | c.726C>T |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs112264814](https://www.ncbi.nlm.nih.gov/snp/rs112264814/) |
| Variant type | single nucleotide variant |
| Location | chr8:144442265-144442265 (GRCh38) |
| ClinVar | [VCV1170823](https://www.ncbi.nlm.nih.gov/clinvar/variation/1170823/) |

**All HGVS expressions:** `NC_000008.10:g.145667648G>A`, `NC_000008.11:g.144442265G>A`, `NM_013432.4:c.726C>T`, `NM_013432.5:c.726C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.98) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.039, GERP -3.06, phastCons 1 — weakly conserved position
- CADD: **PHRED 22.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.08**, acceptor gain **0.00**, donor gain **0.98**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.98**.
- Pangolin: Δ**0.69** (gain), gain 0.69 / loss 0.15. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.729%** (afr) · FAF95 0.678% · FAF99 0.658% · 544/74,644 in the highest group · 614/1,592,282 alleles overall — rare (popmax 0.729%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.729% | 137 |
| Remaining individuals (not grpmax-eligible) | 0.0667% | 1,500 |
| Admixed American | 0.0323% | 3,099 |
| Middle Eastern | 0.0167% | 5,982 |
| South Asian | 0.00445% | 22,462 |
| East Asian | 0.00225% | 44,434 |
| European (non-Finnish) | 0.000343% | 291,327 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TONSL** population constraint: LOEUF 1.024, pLI 2.6737e-33, missense-Z -1.1994. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **242** lies in a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp).

AlphaFold model confidence (whole protein): pLDDT 76.06, 44% of residues very-high.

**3 experimental structure(s)** (PDB): [5JA4](https://www.rcsb.org/structure/5JA4), [9WVH](https://www.rcsb.org/structure/9WVH), [9WVI](https://www.rcsb.org/structure/9WVI) — incl. mutant structure 9WVI.

## What this gene does {#gene-function}

*Describes the biological roles of TONSL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TONSL's established molecular role includes histone binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** histone binding, histone reader activity.

**Biological process:** double-strand break repair via homologous recombination, replication fork processing, protein localization to chromatin.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-15.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 6 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-01-28 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-15 |

**Reported phenotype names (ClinVar):** not provided, TONSL-related disorder, Thymoma, Colorectal cancer, Sarcoma, TONSL-related condition, none provided.

## Same-residue context {#hotspot}

Residue **242** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TONSL p.Ser242fs](/variant/tonsl-p-ser242fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TONSL variant pages (same residue, condition, or type): [TONSL p.Ser242fs](/variant/tonsl-p-ser242fs), [TONSL c.1891-1G>C](/variant/tonsl-c-1891-minus-1g-c), [TONSL p.Arg875Ter](/variant/tonsl-p-arg875ter), [TONSL p.Arg934Trp](/variant/tonsl-p-arg934trp), [TONSL p.Gln177Ter](/variant/tonsl-p-gln177ter), [TONSL p.Gln511Ter](/variant/tonsl-p-gln511ter), [TONSL p.Glu487Lys](/variant/tonsl-p-glu487lys), [TONSL c.2775+5G>T](/variant/tonsl-c-2775-plus-5g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1170823). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*